Accumulated evidence suggests that the E2 spike protein of the murine coronaviruses contains domains which are important in virus attachment and neutralization, and in mediating cell to cell fusion. We have recently shown that variants of MHV-JHM selected in this laboratory (MHV-4) contain lesions in the E2 protein which render them resistant to neutralizing monoclonal antibodies and are attenuated in their neurovirulence. Infections by these variant viruses are restricted predominantly to CNS glial cells, in vivo, and result in chronic demyelinating disease characterized by episodes of demyelination, remyelination, and further demyelination accompanied by mild mononuclear cell inflammatory responses. We propose to study several aspects of the specificity of this neurovirulence by analyzing these E2 mutants at the molecular level using RNA and protein sequencing, by analyzing CNS neurons for the presence of virus specific receptors using anti- idiotypic antibodies against defined monoclonals, and by studying the significance of sequence homologies observed between MHV- JHM E2 glycoprotein and normal tissue constituents such as myelin basic protein and fibronectins. These studies will contribute to our understanding of the events and/or molecules which govern the fate of viral infections of the CNS.